a. Field of the Invention
This invention relates to a process for the purification of .gamma.-oxo-2-dibenzofuranbutyric acid. The latter compound and its water soluble pharmaceutically acceptable salts are useful as antiinflammatory agents.
B. Prior Art
The compound .gamma.-oxo-2-dibenzofuranbutyric acid has been described by F. Mayer and W. Krieger, Chem. Ber., 55B, 1659 (1922) and by H. Gilman, et al., J. Amer. Chem. Soc., 61, 2842 (1939). The compound is represented by formula l: ##SPC1##
The co-pending Application of T. A. Dobson and J. G. Rochefort, Ser. No. 50,296, filed June 26, 1970, now U.S. Pat. No. 3,728,349, issued Apr. 17, 1973, described in detail the results of pharmacologic testing of .gamma.-oxo-2-dibenzofuranbutyric acid as prepared by the procedures of Gilman et al., cited above, and such results are incorporated herein by reference. Application Ser. No. 50,296 also describes and claims dosage forms for the method of treatment of inflammatory conditions employing .gamma.-oxo-2-benzofuranbutyric acid and the description of such dosage forms is also incorporated herein by reference.
It has now been found that the above compound possesses important antiinflammatory properties and a low order of toxicity, which makes it particularly valuable for use as an antiinflammatory agent in the treatment of inflammatory conditions. The compound is also exceptionally well tolerated upon prolonged administration of high doses and possesses a highly favorable therapeutic index. The compound also possesses analgesic and antipyretic activity.
As an added advantage, the compound does not cause formation of gastrointestinal ulcers when tested at therapeutic dose levels for ulcerogenic activity in a modification of a known method.
The compound, .gamma.-oxo-2-dibenzofuranbutyric acid, which has only limited solubility in water, is easily transformed into a highly water-soluble pharmaceutically acceptable salt thereof by titrating with a water-soluble base; for example, an alkali metal, alkaline earth metal, ammonium or substituted ammonium hydroxide, or with an organic base. The preferred salt is the sodium salt, obtainable from the free acid by titrating with sodium hydroxide.
These salts of .gamma.-oxo-2-benzofuranbutyric acid exhibit the same pharmacological activity as the parent acid when administered to animals.
A preparation of the useful agent of this invention, .gamma.-oxo-2-dibenzofuranbutyric acid, is described by H. gilman, et al., cited above. On first glance, this reported preparation appears to be both convenient and practical. According to this report, the useful agent of this invention is obtained directly by the reaction of dibenzofuran and succinic anhydride in a Friedel-Crafts type reaction. Furthermore, Gilman states that this method gives an 83% yield of the purified .gamma.-oxo-2-dibenzofuranbutyric acid.
However, in contradistinction to the report, a close examination of this product with today's methods for detecting homogeneity, for example, gas liquid chromatography (glc), shows that the product of the Gilman procedure is not purified .gamma.-oxo-2-dibenzofuranbutyric acid (l) but rather a mixture. This mixture consists of the desired acid 11 and a significant amount of its isomer, .gamma.-oxo-3-dibenzofuranbutyric acid (ll). ##SPC2##
Although both the desired acid l and the isomer ll have antiinflammatory activity, and although both may be used for this purpose in the manner described herein for the acid l, the said acid l has been found to be somewhat more active and have a quicker onset of action. Accordingly, a process for separating these two acids has become of significant importance.
The presence of this isomer in the product of this preparation presents a difficult problem with regard to its separation from the desired acid l. The difficulty is mainly due to the isomer ll possessing many similar physical characteristics of the desired acid l. Thus, the direct separation of the isomer ll from the desired acid l on a reasonable scale by conventional means has proven to be an unfeasible and impractical operation to date. For example, crystallization of the mixture of acids from various solvents, for example, toluene, ethyl acetate and methanol, does not change substantially the relative proportions of the two acids in the mixture.
Accordingly, it is the purpose of this invention to disclose a method whereby the isomer ll can readily be removed from the above mixture so that the desired acid l is obtained in a pure form.
For many reasons, including the sophisticated and exacting requirements of manufacturing and government organizations to control and maintain the quality of a drug, it is desirable to be able to prepare the drug in its highest possible state of purity.